(Circulation. 1995;92:1169-1178.)
© 1995 American Heart Association, Inc.
Articles |
Alterations in Intracellular Calcium Handling Associated With the Inverse Force-Frequency Relation in Human Dilated Cardiomyopathy
From the Medizinische Klinik III (B.P., B.K., M.M., C.H., H.J., G.H.) and Physiologisches Institut (J.W.), Universität Freiburg, and Klinik für Thorax- und Kardiovaskularchirurgie (H.P., K.M.), Herzzentrum Nordrhein-Westfalen, Bad Oeynhausen, Germany.
Correspondence to Burkert Pieske, MD, Medizinische Klinik III, Universität Freiburg, Hugstetter Str 55, 79106 Freiburg, Germany.
 |
Abstract |
|---|
 Top Abstract IntroductionMethods Results Discussion References |
|---|
Background The present study was performed to test the hypothesis that the altered force-frequency relation in human failing dilated cardiomyopathy may be attributed to alterations in intracellular calcium handling.
Methods and Results The force-frequency relation was investigated in isometrically contracting ventricular muscle strip preparations from 5 nonfailing human hearts and 7 hearts with end-stage failing dilated cardiomyopathy. Intracellular calcium cycling was measured simultaneously by use of the bioluminescent photoprotein aequorin. Stimulation frequency was increased stepwise from 15 to 180 beats per minute (37°C). In nonfailing myocardium, twitch tension and aequorin light emission rose with increasing rates of stimulation. Maximum average twitch tension was reached at 150 min-1 and was increased to 212±34% (P<.05) of the value at 15 min-1. Aequorin light emission was lowest at 15 min-1 and was maximally increased at 180 min-1 to 218±39% (P<.01). In the failing myocardium, average isometric tension was maximum at 60 min-1 (106±7% of the basal value at 15 min-1, P=NS) and then decreased continuously to 62±9% of the basal value at 180 min-1 (P<.002). In the failing myocardium, aequorin light emission was highest at 15 min-1. At 180 min-1, it was decreased to 71±7% of the basal value (P<.01). Including both failing and nonfailing myocardium, there was a close correlation between the frequencies at which aequorin light emission and isometric tension were maximum (r=.92; n=19; P<.001). Action potential duration decreased similarly with increasing stimulation frequencies in nonfailing and end-stage failing myocardium. Sarcoplasmic reticulum 45Ca2+ uptake, measured in homogenates from the same hearts, was significantly reduced in failing myocardium (3.60±0.51 versus 1.94±0.18 (nmol/L) · min-1 · mg protein-1, P<.005).
Conclusions These data indicate that the altered force-frequency relation of the failing human myocardium results from disturbed excitation-contraction coupling with decreased calcium cycling at higher rates of stimulation.
Key Words: aequorin • excitation • contraction • sarcoplasmic reticulum • heart failure
|
Introduction |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
Frequency potentiation of contractile force represents a potent inotropic mechanism in myocardium of most species, including nonfailing human myocardium.1 2 3 4 5 However, recent experiments in isolated human myocardium from end-stage failing hearts indicated that in the failing myocardium, frequency potentiation of contractile force is absent. Moreover, in most muscle strips from failing human hearts, the force-frequency relation was shown to be inverse.4 5 6 7 The relevance of these in vitro findings in the isolated human myocardium has been confirmed by clinical investigations: in patients with normal left ventricular function, hemodynamic parameters of myocardial contractility increased with increasing pacing rates during atrial or ventricular stimulation, whereas frequency potentiation of myocardial performance was absent in patients with heart failure.8 9
Frequency potentiation of contractile force was suggested to result from increased transsarcolemmal Ca2+ influx leading to greater filling of the sarcoplasmic reticulum (SR) and thus, a higher amount of Ca2+ available for release and activation of the contractile proteins.3 10 The subcellular defects underlying the inverse force-frequency relation in the failing human myocardium are unknown.
The altered force-frequency relation could result from a decreased calcium sensitivity or disturbed function of the contractile proteins at higher rates of stimulation despite normal calcium availability. Alternatively, intracellular calcium and thus, activator calcium to the contractile proteins may be reduced at higher frequencies. Myothermal measurements indicating that the total amount of calcium cycling is reduced significantly at a stimulation rate of 60 beats per minute (bpm) in the failing human myocardium support the latter possibility.11 Furthermore, the recent finding of a close correlation between force-frequency behavior of the human myocardium and SR Ca2+-ATPase protein levels may suggest that disturbed calcium cycling is a major underlying mechanism for the altered force-frequency relation of the failing human heart.12 However, none of the above-mentioned studies in human myocardium directly investigated the frequency-dependent changes of the intracellular Ca2+ transients under physiological experimental conditions.
Accordingly, the present study was performed to investigate the hypothesis that the positive force-frequency relation in nonfailing human myocardium results from increased free cytosolic calcium at higher rates of stimulation and that a frequency-dependent decline of systolic calcium transients is related to the inverse force-frequency relation in failing human hearts. The experiments were performed in isolated muscle strips from nonfailing human hearts and from hearts with end-stage failing dilated cardiomyopathy at 37°C and stimulation rates between 15 and 180 min-1 with the bioluminescent photoprotein aequorin. SR calcium uptake was measured in myocardium from the same hearts and related to frequency-dependent changes of the intracellular calcium signal. In addition, the influence of stimulation frequency on action potential duration was recorded.
|
Methods |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
Myocardial Tissue
Human left or right ventricular trabeculae were obtained from 6 nonfailing donor hearts that could not be transplanted for technical reasons and from 14 hearts with end-stage failing dilated cardiomyopathy at the time of heart transplantation. The mean age in the donor group was 39±7 years; three of the donors were women and three were men. No cardiac catheterization had been performed in the organ donor group, but none of the donors had a history of heart disease and all had normal left ventricular function. In the heart failure group, coronary artery disease or valvular disease had been excluded before transplantation. Clinical data of the patients are shown in Table 1
.
|
The study was reviewed and approved by the Ethical Committee of the University Clinics of Freiburg.
Muscle Strip Preparation
Immediately after explantation of
the heart, the ventricles were
carefully opened, and a thin layer of the subendocardial
myocardium was excised for functional measurements. Special
attention was given to avoiding damage of the fine
trabecular network at the inner surface of the ventricle.
In addition, transmural pieces of left ventricular
myocardium from 3 of the 6 nonfailing hearts and from 7 of
the 14 failing hearts were frozen in liquid nitrogen immediately after
cardiectomy. This myocardium was stored at -80°C for
later measurements of oxalate-facilitated SR
45Ca2+ uptake.
The excised myocardium for functional measurements was stored in a special cardioplegic solution oxygenated with carbogen (95% O2/5% CO2) and transported to the laboratory at room temperature. The solution contained (in mmol/L) Na+ 152, K+ 3.6, Cl- 135, HCO3- 25, Mg2+ 0.6, H2PO4- 1.3, SO42- 0.6, Ca2+ 2.5, glucose 11.2, and 2,3-butanedione monoxime 30, plus insulin 10 IU/L. This cardioplegic solution was shown to protect the myocardium during transportation and from cutting injury at the time of muscle strip dissection.13 Its effects on the myocardium were shown to be fully reversible after washout.13 Small trabeculae were dissected with the help of a stereoscopic microscope. All preparation steps were carried out in the cardioprotective solution. The trabeculae were then mounted horizontally in a cylindrical glass cuvette between miniature clamps and connected to an isometric force transducer (OPT1L, Scientific Instruments) and superfused with a carbogen-bubbled modified Krebs-Henseleit solution of the composition given above, with the exception that 2,3-butanedione monoxime was omitted. Punctate stimulation via a platinum electrode at the end of the muscle was used. After the muscle strips were initially prestretched with a force of 1 mN, they were allowed to equilibrate for 30 to 60 minutes at a stimulation frequency of 1 Hz and stimulation voltage 20% above threshold. Thereafter, the muscles were gradually stretched along their length-tension curve in 0.05-mm steps until maximum isometric tension was reached.
Aequorin Measurements
By the time of complete mechanical
stabilization of the
trabecular strips at maximum isometric tension, electrical
stimulation was switched off for 5 minutes, and the
Ca2+-regulated bioluminescent photoprotein aequorin
was macroinjected into the quiescent muscle just beneath the
endocardium.14 The aequorin light signal was detected with
a photomultiplier tube (XP 2802, Philipps) vertically mounted with its
cathode just above the glass cuvette containing the aequorin-loaded
muscle. To increase the optical efficiency of the system, an
ellipsoidal mirror was placed beneath the glass cuvette, reflecting
photons to the photomultiplier tube. Light emissions (in millivolts of
amplifier output) and force signals were recorded
simultaneously on-line on a personal computer and an
oscilloscope with signal-averaging function (Nicolet PRO 10C, Nicolet
Instrument Corp) as well as on a strip-chart recorder (WR 3310,
Graphtec) for original registration. Fifty light transients were
averaged at each experimental step to increase the signal-to-noise
ratio. The experimental protocol was started at the time when the
aequorin light signals were completely stable.
Aequorin was purchased in lyophilized form from Prof John R. Blinks at the Friday Harbor Laboratories. Lyophilized aequorin (1 mg) was dissolved in 700 µL quartz-distilled water to minimize Ca2+ contamination.
Experimental Protocol
After stable light and force signals at
60 min-1
had been obtained for at least 10 minutes, stimulation frequency was
reduced to 15 min-1. From this frequency, the stimulation
rate was increased stepwise up to a maximum frequency of 180
min-1. Isometric twitch myograms and aequorin light
signals were sampled during steady-state conditions at the following
stimulation frequencies: 15, 30, 60, 90, 120, 150, and 180
min-1. Twitch tension is defined as the active tension
developed during the isometric twitch. It is the amplitude of the
twitch signal between peak systolic tension and diastolic
tension at the end of the stimulus interval. Accordingly, aequorin
light emission is defined as the amplitude of the aequorin light signal
between the peak systolic light emission and the diastolic
baseline value. The amplitude of the aequorin light signal (millivolts
of amplifier output) was compared with the amplitude of the isometric
twitch tension (mN/mm2) at each stimulation frequency. In
addition to amplitudes of twitch and aequorin light signal, total
twitch time, time to 50% relaxation, and time to 95% relaxation of
the isometric twitch and time to 50% decline and time to 80% decline
of the aequorin light signal were evaluated (see Table 2). In
one set of experiments, the force-frequency
relation was investigated in muscle strip preparations from 3
nonfailing hearts after preincubation for 30 minutes with the
ß-adrenergic receptor blocker propranolol (1 µmol/L).
Cross-sectional area of the muscle for normalization of force values
was determined as the ratio of blotted muscle weight to muscle length.
Average cross-sectional area of the muscle strips was 0.40±0.04
mm2 (0.15 to 0.66 mm2). Experiments were
performed in 7 muscle strips from 5 nonfailing hearts (2 from the
right, 5 from the left ventricle) and in 12 muscle strips from 9
end-stage failing hearts (5 from the right, 7 from the left
ventricle).
|
SR 45Ca2+ Uptake
Assay
Oxalate-facilitated Ca2+ uptake was measured
immediately after homogenization with the Millipore
filtration system (Millipore Corp). The assay was performed according
to the method described by Pagani and Solaro.15 For
measurement of calcium uptake, small samples of the frozen
myocardium were minced with scissors and knife on a
ice-cold rubber surface. During this procedure, care was taken to
remove fat, vessels, and epicardium. Homogenization
was performed in 10 mL of ice-cold solution containing 25 mmol/L
imidazole (pH 7.0) for four 10-second periods in a Polytron
homogenizer (PT-K, Kinematica). An aliquot of the
homogenate was transferred into the uptake medium
containing (in mmol/L, final concentration) KCl 100, imidazole 40,
potassium oxalate 5, MgCl2 4.5, NaCl2 10,
sodium ATP 2.5, creatine phosphate 3, and 2 IU/mL creatine
phosphokinase (pH 7.0). After an equilibration time of 5 minutes
(37°C), the assay was started by addition of CaCl2 (25
µmol/L, 0.185 µCi 45Ca2+/mL)
and EGTA (15.5 µmol/L). Aliquots of the reaction medium (100 µL)
were taken after 30, 60, 90, and 120 seconds, filtered through a
0.45-µm Millipore filter, and rapidly washed with ice-cold 0.6 mol/L
KCl, 5 mmol/L NaN3, and 20 mmol/L imidazole to stop
the uptake. Radioactivity was determined by liquid scintillation
spectroscopy. The calcium uptake rate was calculated from the linear
regression analysis of the four time points from the slope
relating calcium uptake to time. Each uptake rate used in the
calculations is the mean of three uptake measurements. Free calcium
concentrations were calculated by a computer program and expressed as
nmol/L Ca2+ · min-1 · mg
protein-1. Protein was determined by the method described
by Bradford.16
Action Potential Measurements
In a further set of
experiments, the influence of stimulation
frequency on action potential characteristics was investigated in 7
muscle strip preparations from 5 end-stage failing hearts (4 from the
left and 3 from the right ventricle) and in 1 left
ventricular muscle strip preparation from a nonfailing
human heart. The muscle strip preparations were placed in an organ bath
and superfused with a carbogen-bubbled modified Krebs-Henseleit
solution of the above composition at 37°C. The preparations were
electrically stimulated via a punctate electrode with rectangular
pulses of 0.2-ms duration, voltage 20% above threshold. Transmembrane
action potentials were recorded by means of conventional 3 mol/L
KCl–filled glass microelectrodes (resistance, 5 to 11 M
). Action
potentials were displayed on a digital storage oscilloscope (Nicolet
2090) and stored on a 486 personal computer for data analysis.
Only experiments in which a single impalement could be maintained
throughout control and experimental periods were evaluated. After
impalement, stimulation frequency was increased stepwise from 15 to 180
bpm, and action potentials were recorded at each stimulation
frequency after complete stabilization of the signals.
Simultaneously, frequency-dependent changes in isometric
force were evaluated in muscle strip preparations from the same hearts
according to the protocol described above.
Statistical Analysis
Average values are given as
mean±SEM. Comparison within one
group of myocardium was performed with the paired
t test. If multiple values within one group were compared,
the paired t test followed by the Bonferroni-Holm
equation17 was used. Comparison between different groups
of myocardium was performed with the unpaired t
test. Correlations were examined by linear regression analysis.
Differences were considered significant at P<.05.
|
Results |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
In the nonfailing and failing human myocardium, isometric twitch tension and aequorin light emission critically depended on stimulation frequency. Fig 1
shows original
recordings of experiments in an aequorin-loaded muscle strip
from a nonfailing heart (top) and a failing heart (bottom). In both
muscle preparations, stimulation frequency was increased from 30 to 120
min-1 and then reduced to 30 min-1 again.
When stimulation frequency was increased from 30 to 120
min-1, the nonfailing myocardium
responded with a pronounced increase in the amplitude of the light
signal. The increase in light emission was accompanied by an increase
in twitch tension amplitude with only minimal changes in
diastolic tension. In the failing myocardium,
the increase in stimulation rate from 30 to 120 min-1
resulted in a pronounced decrease in the amplitude of the light signal.
The change in light amplitude was accompanied by a pronounced decrease
in the amplitude of the isometric twitch, with only a slight increase
in diastolic tension. The complete reversibility in light
and tension changes in both preparations were shown by reducing the
stimulation rate back to 30 min-1.
|
The differences between nonfailing and failing myocardium
with respect to isometric force development and aequorin light emission
could be seen over the whole frequency range. Fig 2
shows typical experiments in a muscle strip from a nonfailing and from
an end-stage failing heart. The change in force or aequorin light
emission is given in absolute values. As becomes evident, the isometric
twitch tension of the preparation from the nonfailing heart increased
from 7.6 mN/mm2 at 15 min-1 to 20.9
mN/mm2 at 150 min-1. This increase in force
was associated with a parallel increase in aequorin light emission from
380 to 776 mV. In the muscle strip from the failing heart, isometric
twitch tension was maximal at 30 min-1 (6.4
mN/mm2) and then declined to 4.1 mN/mm2 at 180
min-1. This decline in force was associated with a
parallel decline in the aequorin light signal from 398 mV at 15
min-1 to 198 mV at 180 min-1.
|
The average values for force and aequorin light signals in nonfailing
myocardium are shown in Fig 3. In all
experiments, twitch tension and aequorin light emission were lowest at
15 min-1 and increased considerably with higher
stimulation rates. Maximum twitch tension and aequorin light emission
were reached at stimulation frequencies between 120 and 180
min-1. Maximum average twitch tension was reached at a
frequency of 150 min-1 and was increased to 212±34% of
the basal value at 15 min-1 (P<.05). At 180
min-1, tension was still increased to 185±29% of
the basal value (P<.05). The frequency dependence of the
average aequorin light signal parallels that of the twitch tension.
Light emission was lowest at 15 min-1 and reached its
average maximum at a stimulation frequency of 180
min-1, when it was increased to 218±39% of the
basal value at 15 min-1 (P<.01).
Frequency-dependent changes of relaxation parameters of
aequorin light signals and isometric twitches are given in Table
2
.
|
To evaluate the possibility that the positive force-frequency relation in nonfailing myocardium might be due to increased catecholamine release during higher stimulation rates, experiments were performed after ß-adrenergic receptor blockade with propranolol. Under the influence of 1 µmol/L propranolol, the positive force-frequency relation was similar. Maximum tension was reached at 150 min-1 and was increased to 256±18% of the basal value at 15 min-1 (n=3). This indicates that catecholamine release and subsequent ß-adrenergic receptor stimulation is not the cause of the positive force-frequency relation in nonfailing myocardium.
The average values for force and aequorin light signals in the failing
myocardium are shown in Fig 4. In isolated
myocardium from hearts with end-stage failing dilated
cardiomyopathy, isometric twitch tension and
aequorin light signals tended to decrease with higher stimulation
rates. Although there was some variation in the optimal stimulation
frequency for each individual muscle strip (15 to 90
min-1), average isometric twitch tension was maximum at a
stimulation frequency of 60 min-1, where it
attained 106±7% of the basal value at 15 min-1
(P=NS). At stimulation rates >60 min-1,
force of contraction declined continuously in most muscle strip
preparations. At 180 min-1, twitch tension was
reduced to 62±9% of the basal value at 15 min-1
(P<.002). As is also evident from Fig 4, the
average
aequorin light signal decreased with higher rates of stimulation. The
decline of the aequorin light emission parallels that of the isometric
force. At 180 min-1, the average aequorin light
signal was decreased to 71±7% of the value at 15 min-1
(P<.01). Frequency-dependent changes of relaxation
parameters of aequorin light signals and isometric twitches
are given in Table 2.
|
Including nonfailing (n=7) and failing (n=12) myocardium,
there was a significant correlation (r=.92;
P<.001) between the frequencies at which peak aequorin
light signal and peak isometric twitch tension were reached (Fig
5). The correlation between the two
parameters was also statistically significant when the
analysis was performed in myocardium from hearts
with dilated cardiomyopathy exclusively
(r=.88; P<.001). These correlations demonstrate
that parallel changes in light frequency and force frequency occur in
the human myocardium.
|
, End-stage failing
myocardium; 
, nonfailing myocardium.
Oxalate-facilitated 45Ca2+ uptake by the
SR was measured in homogenates from 3 of the 5 nonfailing
and 7 of the 9 failing hearts. In the nonfailing
myocardium, 45Ca2+ uptake
was 3.60±0.51 (nmol/L) · min-1 · mg
protein-1. However, in the failing myocardium,
45Ca2+ uptake was reduced significantly,
to 1.94±0.18 (nmol/L) · min-1 · mg
protein-1 (P<.05 versus nonfailing; Table
3). There was a clear separation between nonfailing and
failing myocardium with respect to Ca2+
uptake and the stimulation frequency when aequorin light emission (ie,
intracellular Ca2+ transient) was maximal: In the
nonfailing myocardium, Ca2+ uptake was
high and maximal aequorin light emission was reached at a high
stimulation rate. In end-stage failing myocardium,
Ca2+ uptake was low and maximal aequorin light
emission was reached at a low stimulation rate (Fig 6).
|
|
Frequency-dependent changes in isometric force may be related to
changes in action potential duration resulting from changes in
transsarcolemmal Ca2+ flux. Therefore,
frequency-dependent changes in action potential duration (time to 50%
repolarization and time to 90% repolarization, APD50 and
APD90) were measured in muscle strip preparations from 5
end-stage failing hearts and 1 nonfailing heart.
Simultaneously, the force-frequency relation was
characterized in muscle strip preparations from the same hearts. Fig
7 shows typical superimposed recordings of
action potentials at 30 and 120 bpm and the corresponding isometric
twitches from an end-stage failing and a nonfailing heart. The action
potentials were characterized by a rapid upstroke followed by a
gradually increasing speed of repolarization without a marked point of
termination of the plateau phase. Such action potentials are typical
for ventricular myocardium of
mammals18 and humans.19 In both types of
myocardium, action potential duration decreased with the
higher stimulation frequency, whereas isometric twitch tension
increased in the nonfailing myocardium but decreased in the
end-stage failing myocardium. The average values for all
stimulation frequencies are shown in Fig 8. It is
obvious that in both types of myocardium, APD50
and APD90 shorten with increasing stimulation frequency. In
the nonfailing myocardium, the frequency-dependent decline
in action potential duration is associated with an increase in
isometric twitch tension. In the end-stage failing
myocardium, isometric twitch tension tends to decline with
higher stimulation frequencies and shorter action potential duration.
To evaluate whether the force-frequency behavior of the individual
hearts may be related to frequency-dependent changes in action
potential configuration, the change in action potential duration
(APD50, APD90) after an increase in
stimulation frequency from 30 to 120 min-1 was correlated
with the parallel frequency-dependent change in twitch tension. In
dilated cardiomyopathy, no significant correlation
between the frequency-dependent change in action potential duration and
force was observed (for APD50, r=.6377,
P<.173; for APD90, r=.5218,
P<.288; n=6).
|
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
Frequency potentiation of contractile force is considered to be a major physiological mechanism for the regulation of myocardial performance.1 3 It is now well established that frequency potentiation of contractile force occurs in the nonfailing human heart,4 5 but substantial alterations of the force-frequency relation have been observed in the failing human heart under in vitro as well as in vivo conditions.4 5 6 7 8 9
Mulieri et al4 were the first to demonstrate the blunted force-frequency relation in human end-stage failing myocardium under physiological conditions. These authors speculated that a reduced Ca2+ activation of the contractile proteins at higher rates of stimulation may be the underlying defect. However, simultaneous measurements of intracellular Ca2+ transients and isometric force have never been performed in human myocardium under physiological conditions.
Gwathmey et al7 and Morgan,20 using the photoprotein aequorin to measure intracellular Ca2+ concentrations, did not observe stimulation-interval–related differences in the peak systolic Ca2+ transients between nonfailing and end-stage failing human myocardium. However, these experiments were performed at an unphysiological low temperature (30°C) and at low stimulation frequencies (0.6 to 60 bpm). It is important to note that frequency-dependent changes of contractile force depend critically on experimental temperature and the frequency range investigated.13 21
Since simultaneous force and Ca2+ measurements have never been performed under physiological conditions as to temperature and stimulation rate, it was the purpose of the present study to investigate frequency dependence of contractile force and intracellular Ca2+ transients in nonfailing and end-stage failing human myocardium at a physiological temperature (37°C) and over the whole physiological frequency range. We tested the hypothesis that the inverse force-frequency relation in the failing human myocardium is associated with reduced aequorin light emission, and thus, reduced intracellular Ca2+ transients, at higher rates of stimulation.
The present data confirm that the force-frequency relation is positive in nonfailing human myocardium and that it is flattened or inverse in failing myocardium. Furthermore, the present aequorin measurements strongly indicate that the positive force-frequency relation in the nonfailing myocardium results from frequency-dependent increases in the intracellular Ca2+ transients and that the altered force-frequency relation in the failing myocardium is attributable to disturbed calcium cycling processes in the diseased human heart. This can be seen from the parallel changes of isometric force and aequorin light signals in the different types of myocardium. Changes in the amplitude of the aequorin light signal reflect changes in the free intracellular Ca2+ concentration relevant for activation of contractile proteins.22 In nonfailing myocardium, higher stimulation rates result in an increase in the amplitude of the aequorin light signal, indicating an increase in the intracellular free Ca2+ concentrations and a parallel rise in twitch tension. In contrast, the decline in isometric tension at higher rates of stimulation in the failing myocardium is associated with a decline in the amplitude of the aequorin light signals, indicating a decrease in the free intracellular Ca2+ concentration. Furthermore, the close correlation between the frequencies at which maximum isometric force and light emission are reached strongly indicates that the frequency dependence of the intracellular free calcium concentration determines the force-frequency relation in the human myocardium. On the other hand, these findings make it unlikely that changes in calcium sensitivity or changes in the behavior of the contractile proteins are a major cause of the altered force-frequency relation in the failing human myocardium.
The present findings are in contrast to data published by Gwathmey
et al7 and Morgan.20 These investigators
observed an inverse force-frequency relation but a positive aequorin
light-frequency relation in failing compared with nonfailing human
myocardium (after stimulation frequency was increased from
20 to 60 bpm). From this dissociation between force and light after an
increase in stimulation frequency, the authors concluded that
abnormalities of contractile function in failing human
myocardium are not due to decreased availability of
intracellular Ca2+ but more likely reflect
differences of myofibrillar Ca2+ responsiveness.
However, the decline in force was due primarily to an increase in
diastolic tone (contracture; Reference 7, Fig 11). The
decrease in force amplitude due to contracture occurred despite an
increase in peak amplitude of the Ca2+ transient
when stimulation frequency was raised from 20 to 60 bpm (Reference 7,
Table 1). We believe that the different results between our
work and
that of Gwathmey et al are related to differences in experimental
conditions. In the studies by Gwathmey et al, the force-frequency
relation was studied in the range from 20 to 60 bpm. A positive
force-frequency relation (this study; see also Mulieri et
al4 ) or aequorin light-frequency relations in failing
human myocardium in the low stimulation frequency range up
to 60 bpm is not an uncommon finding. In fact, in our study, in 5 of 11
muscle strip preparations from failing hearts, aequorin light emission
was maximal at 60 bpm and declined only at higher stimulation
frequencies. Therefore, since measurements were performed only at low
stimulation frequencies in the study by Gwathmey et al, the negative
portion of the aequorin light-frequency range may have been above the
frequency range investigated. In addition, lowering the temperature
from 37°C to 30°C results in a considerable prolongation of the
isometric twitch due to a reduced rate of Ca2+
elimination from the cytosol and alterations of cross-bridge behavior.
Accordingly, as shown by Gwathmey et al, a stimulation rate of 60 bpm
results in incomplete relaxation and thus, a rise in
diastolic tension. Alternatively, acidosis or phosphate
accumulation in the core of the muscle strip preparations might have
been the cause of the dissociation between tension development and
intracellular Ca2+ transients.
In this study, only minor changes in diastolic tension and diastolic aequorin light emission were observed at higher stimulation rates. This is in good agreement with the data of Mulieri et al.23 Of note, because of its binding characteristics, the Ca2+ indicator aequorin is very sensitive to changes in peak systolic Ca2+ concentrations but less sensitive in the low Ca2+ concentration range during diastole.22 Therefore, minor changes in diastolic Ca2+ concentration may not be reliably detected by use of the photoprotein aequorin.
In the present study, we did not observe two distinct components of the aequorin light signal (L1 and L2) in dilated cardiomyopathy. This is in contrast to Gwathmey et al,24 who demonstrated two distinct light components in failing human myocardium. The distinct light components were most pronounced in hypertrophic obstructive cardiomyopathy but were also detected in dilated cardiomyopathy. However, Beuckelmann et al,25 using the fluorescent Ca2+ indicator fura-2, did not observe distinct light components in isolated myocytes from hearts with end-stage failing dilated cardiomyopathy at 35°C. Furthermore, a contractile counterpart to L2 has never been shown. Therefore, we believe that the second component of the aequorin light signal may be present primarily at low temperature.
Disturbed calcium cycling as the cause of reduced tension development in the failing human myocardium is consistent with recent myothermal measurements showing that the total amount of calcium cycling is reduced at physiological stimulation rates in the failing human heart.11 Furthermore, reduced peak systolic calcium concentrations were suggested from fura-2 measurements in isolated myocytes from failing human myocardium.25
The question arises as to which subcellular alterations may be the underlying cause for the disturbed Ca2+ cycling in the failing human myocardium. The positive force-frequency relation observed in most types of mammals and in nonfailing human myocardium may result from an increased amount of Ca2+ released from the SR at higher rates of stimulation.3 10 Increased Ca2+ release is believed to be the consequence of an increased loading of the SR with Ca2+, which in turn results from a larger amount of Ca2+ entering the myocytes per unit of time at higher stimulation frequencies.3
Accordingly, the present data indicate that the altered force-frequency behavior in the failing human myocardium may result from decreased instead of increased SR Ca2+ release at higher stimulation frequencies. This is consistent with data from Orchard and Lakatta,26 who suggested that the negative force-frequency relation in the rat is due to diminished SR Ca2+ release. Diminished SR Ca2+ release could result from (1) a reduced amount of trigger calcium entering the cell through the L-type calcium channels, (2) a defect of the SR Ca2+ release channel, or (3) a decreased amount of Ca2+ available at the SR Ca2+ release sites. The latter could result from disturbed Ca2+ reuptake into the SR by the SR Ca2+ pumps and therefore SR Ca2+ depletion or from increased transsarcolemmal Ca2+ extrusion by the Na+/Ca2+ exchanger or the sarcolemmal Ca2+ ATPase.
The action potential in heart muscle generally shows a plateau phase at positive potential, which has been attributed to the inward Ca2+ current, ICa.27 Furthermore, it was shown that the relation between action potential and force yields information about Ca2+-related currents.28 29 In our study, action potential duration decreased with higher stimulation frequencies in both types of myocardium. This is consistent with data from Schouten et al,30 who found a 27% decrease in APD20 after increasing stimulation frequency from 0.1 to 1.0 Hz in isolated human ventricular myocardium. However, although action potential duration decreased with higher stimulation rates in both nonfailing and failing myocardium, isometric twitch tension increased in nonfailing and declined in failing myocardium at higher stimulation rates. In addition, no significant correlation between action potential duration and the frequency-dependent change in isometric twitch tension could be obtained in end-stage failing myocardium. There was a tendency for action potential duration to be longer in failing than in nonfailing myocardium at stimulation rates <120 bpm. This is in agreement with previously published reports in human isolated cardiomyocytes31 or muscle strip preparations.7 Therefore, since the duration of the plateau phase of the action potential is considered to be an index for transsarcolemmal Ca2+ influx, it is unlikely that the inverse force-frequency relation is due to alterations of transsarcolemmal Ca2+ influx. Furthermore, Beuckelmann et al32 did not find altered Ca2+ currents in isolated myocytes from failing human myocardium due to dilated cardiomyopathy.
The question arises as to whether a disturbed Ca2+ release from the SR may contribute to the finding of the inverse force-frequency relation in the failing myocardium. A decrease in the Ca2+ transient could originate from a reduced Ca2+ release via the SR Ca2+ release channels (ryanodine receptor) despite a normal amount of Ca2+ stored within the SR or an increased Ca2+ leak from the SR that prevents normal Ca2+ accumulation. Few experimental data regarding these two possibilities are actually available for human myocardium. When human nonfailing and human end-stage failing dilated cardiomyopathies are directly compared, no significant alteration in mRNA expression of the ryanodine receptor has been observed.33 Arai et al,34 however, found a significant inverse relation between mRNA expression of atrial natriuretic factor and Ca2+ release channels in failing dilated cardiomyopathy. Holmberg and Williams35 did not find abnormal functional activity of single SR Ca2+ release channels under voltage-clamp conditions from end-stage failing human hearts. However, the latter authors compared their data with the activity of SR Ca2+ release channels from normal sheep and canine myocardium, which may not completely reflect the situation in the normal human heart. D'Agnolo et al36 found an increased threshold for caffeine to release Ca2+ from the SR in idiopathic dilated cardiomyopathy and postulated an abnormal gating mechanism of the Ca2+ release channel in this disease state. With respect to an increased leakage of Ca2+ from the SR, some disease states such as malignant hyperthermia have been related to pathological Ca2+ efflux through SR Ca2+ release channels in human37 and porcine38 skeletal muscle. However, similar findings have not been described for the human heart. Therefore, at the present time, we cannot exclude the possibility that alterations at the level of the SR Ca2+ release channels may contribute to the pathological force-frequency behavior in human dilated cardiomyopathy.
There is increasing evidence in support of the hypothesis that diminished Ca2+ reuptake into the SR may be of major relevance for contractile dysfunction in the failing human heart. It was shown recently that the expression of the Ca2+-ATPase of the SR is reduced at the level of the mRNA as well as the protein in the failing human myocardium.12 34 39 40 41 Furthermore, a significant correlation between the protein levels of the SR Ca2+-ATPase and the force-frequency behavior of the failing human myocardium has now been demonstrated.12 These data, in conjunction with the present findings, provide considerable evidence that the reduced tension development at higher frequencies in the failing myocardium may be due to decreased SR Ca2+ release resulting from SR Ca2+ depletion. The latter may occur because at higher stimulation rates, the time available for Ca2+ transport into the SR per cardiac cycle shortens, which, in the presence of a decreased number of SR calcium pumps, may cause insufficient Ca2+ reuptake.
This hypothesis is further supported by our finding that in the failing human myocardium, Ca2+ uptake capacity to the SR is significantly reduced compared with nonfailing myocardium. A low Ca2+ uptake capacity was associated with a blunted frequency potentiation of contractile force. A reduced Ca2+ uptake capacity in failing human myocardium was first described by Limas et al,42 but Movsesian et al43 did not observe a reduced SR Ca2+ uptake capacity in human dilated cardiomyopathy. The latter authors, however, performed their uptake measurements in highly purified SR vesicles, which may attenuate the effect of a decreased expression of SR Ca2+ pumps on SR Ca2+ uptake.
Under conditions of decreased SR calcium accumulation, one would expect diastolic calcium to increase and cause diastolic activation of the contractile proteins. Since in the present study, as well as in previous investigations,4 23 no major changes in diastolic tension were observed, alternative routes for calcium elimination from the myoplasm must exist. Intracellular free Ca2+ may be bound by Ca2+ sinks within the cells, such as troponin C, mitochondria, or other Ca2+-binding proteins.44 45 46 Alternatively, Ca2+ may be eliminated across the sarcolemma to the extracellular space by Ca2+ transport systems, such as the sarcolemmal Ca2+-ATPase or the Na+/Ca2+ exchanger.47 48 Compensatory Ca2+ elimination by the Na+/Ca2+ exchanger may be likely, because it was shown recently that the expression of this protein is increased in failing human hearts concomitantly with a decreased expression of SR Ca2+-ATPase.41 Furthermore, a reduced Ca2+ uptake capacity of the SR would favor extrusion of cytosolic Ca2+ to the extracellular space via Na+/Ca2+ exchange and possibly sarcolemmal Ca2+-ATPase. This could result in a net loss of Ca2+ from the SR and thus, from the cell. Therefore, in the failing myocardium, both a decrease in SR Ca2+ uptake capacity and an increase in Na+/Ca2+ exchange activity may contribute to the decline in systolic tension generation and the amplitude of the aequorin light signal at higher stimulation rates.
In summary, the present study shows that frequency dependence of isometric force generation is closely related to the free intracellular Ca2+ concentrations in the human myocardium. In nonfailing myocardium, increasing stimulation frequencies lead to an increase in the intracellular Ca2+ transients and thus, to an increase in systolic force generation. In the failing myocardium, however, in which substantial alterations occur with respect to proteins involved in intracellular Ca2+ handling, increasing stimulation frequencies lead to a decrease in intracellular Ca2+ transients and thus, to a decrease in systolic force generation. Since SR Ca2+ uptake capacity was reduced in these hearts, this defect may contribute to the observed alterations in excitation-contraction coupling. However, we cannot exclude the possibility that decreased transsarcolemmal Ca2+ influx, increased Ca2+ elimination by the Na+/Ca2+ exchanger, or defects on the level of the Ca2+ release channel of the SR contribute to the alterations in intracellular Ca2+ handling underlying the inverse force-frequency relation in human dilated cardiomyopathy.
|
Acknowledgments |
|---|
This study was supported by Deutsche Forschungsgemeinschaft grant HA 1233/3-1. The authors wish to thank Jim Morgan and Jianxun Wang, Beth Israel Hospital, Harvard University, Boston, Mass, as well as John Blinks, University of Washington, Friday Harbor, for their support in establishing the aequorin technology in isolated heart muscle.
Received September 29, 1994; revision received February 14, 1995; accepted February 27, 1995.
|
References |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
1. Blinks JR, Koch-Weser J. Analysis of the effects of changes in the rate and rhythm upon myocardial contractility. J Pharmacol Exp Ther. 1961;134:373-389.
2. Buckley NM, Penefsky ZJ, Litwak RS. Comparative force-frequency relationships in human and other mammalian ventricular myocardium. Pflugers Arch. 1972;332:259-270. [Medline] [Order article via Infotrieve]
3. Wohlfahrt B, Noble TM. The cardiac excitation-contraction-cycle. Pharmacol Ther. 1982;16:1-43. [Medline] [Order article via Infotrieve]
4.
Mulieri LA, Hasenfuss G, Leavitt B, Allen PD, Alpert
NR. Altered myocardial force-frequency relation in human heart
failure. Circulation. 1992;85:1743-1750.
5. Pieske B, Hasenfuss G, Holubarsch C, Schwinger R, Böhm M, Just H. Alterations of the force-frequency-relationship in the failing human heart depend on the underlying cardiac disease. Basic Res Cardiol. 1992;87:213-221.
6. Feldman MD, Gwathmey JK, Phillips P, Schoen F, Morgan JP. Reversal of the force-frequency relationship in working myocardium from patients with end-stage heart failure. J Appl Cardiol. 1988;3:273-283.
7. Gwathmey JK, Slawsky MT, Hajjar RJ, Briggs GM, Morgan JP. Role of intracellular calcium handling in force-interval relationships of human ventricular myocardium. J Clin Invest. 1990;85:1599-1613.
8. Feldman MD, Alderman JR, Aroesty JM, Royal HD, Ferguson JJ, Owen RM, Grossman W, McKay RG. Depression of systolic and diastolic myocardial reserve during atrial pacing tachycardia in patients with dilated cardiomyopathy. J Clin Invest. 1988;82:1661-1669.
9.
Hasenfuss G, Holubarsch C, Hermann HP, Astheimer K,
Pieske B, Just H. Influence of the force-frequency relation on
hemodynamics and left ventricular function
in patients with nonfailing hearts and in patients with dilated
cardiomyopathy. Eur Heart J. 1994;15:164-170.
10.
Winegard S, Shanes AM. Calcium flux and
contractility in guinea pig atria.
J Gen Physiol. 1962;45:371-394.
11.
Hasenfuss G, Mulieri LA, Leavitt JB, Allen PD, Haeberle
JR, Alpert NR. Alteration of contractile function and
excitation-contraction coupling in dilated
cardiomyopathy. Circ
Res. 1992;70:1225-1232.
12.
Hasenfuss G, Reinecke H, Studer R, Meyer M, Pieske B,
Holtz J, Holubarsch C, Posival H, Just H, Drexler H. Relation
between myocardial function and expression of sarcoplasmic reticulum
Ca2+ ATPase in failing and nonfailing human
myocardium. Circ Res. 1994;75:434-442.
13.
Mulieri LA, Hasenfuss G, Ittleman F, Blanchard
EM, Alpert NR. Protection of human left ventricular
myocardium from cutting injury with 2,3-butanedione
monoxime. Circ Res. 1989;65:1441-1444.
14. Kihara Y, Morgan J. A comparative study of three methods for intracellular loading of the calcium indicator aequorin in ferret papillary muscles. Biochem Biophys Res Commun. 1989;162:402-407. [Medline] [Order article via Infotrieve]
15. Pagani ED, Solaro RJ. Methods for measuring functional properties of sarcoplasmic reticulum and myofibrils in small samples of myocardium. Methods Pharmacol. 1984;5:49-60.
16. Bradford MM. A rapid and sensitive method for the quantification of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976;72:248-254. [Medline] [Order article via Infotrieve]
17. Holm S. A simple sequentially rejective multiple test procedure. Scand J Stat. 1979;6:65-70.
18.
Boyett MR, Jewell BR. A study of the factors
responsible for rate-dependent shortening of the action potential in
mammalian ventricular muscle. J
Physiol (Lond). 1978;285:359-380.
19.
Trautwein W, Kassebaum DG, Nelson RM, Hecht HH.
Electrophysiological study of human
heart muscle. Circ Res. 1962;10:306-312.
20. Morgan JP. Abnormal intracellular modulation of calcium as a major cause of contractile dysfunction. N Engl J Med. 1991;325:625-632. [Medline] [Order article via Infotrieve]
21.
Blinks JR, Koch-Weser J. Physical factors in the
analysis of the actions of drugs on myocardial
contractility. Pharmacol Rev. 1963;15:531-599.
22. Blinks JR, Wier WG, Hess P, Prendergast FG. Measurement of Ca2+ concentrations in living cells. Prog Biophys Mol Biol. 1982;40:1-114. [Medline] [Order article via Infotrieve]
23. Mulieri LA, Leavitt B, Hasenfuss G, Allen PD, Alpert NR. Contraction-frequency dependence of twitch and diastolic tension in human dilated cardiomyopathy (tension-frequency-relation in cardiomyopathy). Basic Res Cardiol. 1992;87:199-212.
24.
Gwathmey JK, Copelas L, MacKinnon R, Schoen FJ, Feldman
MD, Grossman W, Morgan JP. Abnormal intracellular calcium
handling in myocardium from patients with end-stage heart
failure. Circ Res. 1987;61:70-76.
25.
Beuckelmann DJ, Näbauer M, Erdmann E.
Intracellular calcium handling in isolated
ventricular myocytes from patients with terminal heart
failure. Circulation. 1992;85:1046-1055.
26.
Orchard CH, Lakatta EG. Intracellular calcium
transients and developed tension in rat heart muscle.
J Gen Physiol. 1985;86:637-651.
27.
Fedida D, Noble D, Shimoni Y, Spindler AJ.
Inward currents related to contraction in guinea pig
ventricular myocytes. J Physiol
(Lond). 1987;385:565-589.
28.
Schouten VJA. The relationship between action
potential duration and force of contraction in rat
myocardium. Eur Heart J. 1984;5:984-992.
29.
Schouten VJA, ter Keurs HEDJ. The slow
repolarization phase of the action potential in rat heart.
J Physiol (Lond). 1985;360:13-25.
30. Schouten VJA, ter Keurs HEDJ, Quaegebeur JM. Influence of electrogenic Na/Ca exchange on the action potential in human heart muscle. Cardiovasc Res. 1990;24:758-767.
31. Li Q, Biagi B, Hohl C, Starling R, Stokes B, Altschuld R. Effects of isoproterenol and caffeine on calcium transients and action potentials in human ventricular cardiomyocytes. In: Sperelakis N, ed. Frontiers in Smooth Muscle Research. New York, NY: Alan R. Liss; 1990.
32. Beuckelmann DJ, Näbauer M, Erdmann E. Characteristics of calcium-current in isolated human ventricular myocytes from patients with terminal heart failure. J Mol Cell Cardiol. 1991;23:929-937. [Medline] [Order article via Infotrieve]
33.
Brillantes AM, Allen P, Takahashi T, Izumo S, Marks AR.
Differences in cardiac calcium release channels (ryanodine
receptor) expression in myocardium from patients with
end-stage heart failure caused by ischemic versus dilated
cardiomyopathy. Circ
Res. 1992;71:18-26.
34.
Arai M, Alpert NR, MacLennan DH, Barton P, Periasamy M.
Alterations in sarcoplasmic reticulum gene expression in human
heart failure: a possible mechanism for alterations in systolic and
diastolic properties of the failing
myocardium. Circ Res. 1993;72:463-469.
35.
Holmberg S, Williams AJ. Single channel
recordings from human cardiac sarcoplasmic reticulum.
Circ Res. 1989;65:1445-1449.
36.
D'Agnolo A, Luciani GB, Mazzucco A, Gallucci V,
Salviati G. Contractile properties and Ca2+
release activity of the sarcoplasmic reticulum in dilated
cardiomyopathy.
Circulation. 1992;85:518-525.
37. Endo M, Yagi S, Ishizuka T, Horiuti K, Koga Y, Amaha K. Changes in the Ca2+-induced Ca2+ release mechanism in the sarcoplasmic reticulum of the muscle from a patient with malignant hyperthermia. Biomed Res. 1983;4:83-92.
38. Fill M, Coronado R, Mickelson JR, Vilven J, Ma J, Jacobson BA, Louis CF. Abnormal ryanodine receptor channels in malignant hyperthermia. Biophys J. 1990;50:471-475. [Medline] [Order article via Infotrieve]
39. Mercadier JJ, Lompré AM, Duc P, Boheler KR, Fraysse JB, Wisnewsky C, Allen PD, Komajda M, Schwartz K. Altered sarcoplasmic reticulum Ca2+-ATPase gene expression in the human ventricle during end-stage heart failure. J Clin Invest. 1990;85:305-309.
40. Takahashi T, Allen PD, Marks AR, Deniss AR, Schoen FJ, Grossman W, Marsh JD, Izumo S. Altered expression of genes encoding the Ca2+ regulatory proteins in the myocardium of patients with end-stage heart failure: correlation with expression of the Ca2+-ATPase gene. Circ Res. 1992;71:1357-1365.
41.
Studer R, Reinecke H, Bilger J, Eschenhagen T,
Böhm M, Hasenfuss G, Just H, Holtz J, Drexler H. Gene
expression of the cardiac
Na+-Ca2+-exchanger in end-stage human
heart failure. Circ Res. 1994;75:443-445.
42. Limas CJ, Olivari M, Goldenberg IF, Levine TB, Benditt DG, Simon A. Calcium uptake by sarcoplasmic reticulum in human dilated cardiomyopathy. Cardiovasc Res. 1987;21:601-605. [Medline] [Order article via Infotrieve]
43.
Movsesian MA, Bristow MR, Krall J.
Ca2+ uptake by cardiac sarcoplasmic reticulum
from patients with idiopathic dilated
cardiomyopathy. Circ
Res. 1989;65:1141-1144.
44. Wolska BM, Lewartowski B. Calcium in the in situ mitochondria of rested and stimulated myocardium. J Mol Cell Cardiol. 1991;23:217-226. [Medline] [Order article via Infotrieve]
45. Robertson SP, Johnson JD, Potter JD. The time-course of Ca2+ exchange with calmodulin, troponin, parvalbumin, and myosin in response to transient increases in Ca2+. Biophys J. 1981;34:559-569. [Medline] [Order article via Infotrieve]
46.
Holroyde MJ, Robertson SP, Johnson JD, Solaro RJ,
Potter JD. The calcium and magnesium binding sites on cardiac
troponin and their role in the regulation of myofibrillar
adenosine triphosphatase. J Biol
Chem. 1980;255:11688-11693.
47. Carafoli E. The homeostasis of calcium in heart cells. J Mol Cell Cardiol. 1985;17:203-212. [Medline] [Order article via Infotrieve]
48.
Bers DM, Bridge JHB. Relaxation of rabbit
ventricular muscle by Na-Ca exchange and sarcoplasmic
reticulum calcium pump; ryanodine and voltage sensitivity.
Circ Res. 1989;65:334-342.
This article has been cited by other articles:
 |
|
 |
|
  M. N. Sharikabad, J. M. Aronsen, E. Haugen, J. Pedersen, A.-S. W. Moller, H. K. Mork, H. C. D. Aass, O. M. Sejersted, I. Sjaastad, and O. Brors Cardiomyocytes from postinfarction failing rat hearts have improved ischemia tolerance Am J Physiol Heart Circ Physiol, March 1, 2009; 296(3): H787 - H795. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Ikeda, M. Hoshijima, and K. R. Chien Toward Biologically Targeted Therapy of Calcium Cycling Defects in Heart Failure Physiology, February 1, 2008; 23(1): 6 - 16. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Bisping, G. Tenderich, P. Barckhausen, B. Stumme, S. Bruns, D. von Lewinski, and B. Pieske Atrial myocardium is the predominant inotropic target of adrenomedullin in the human heart Am J Physiol Heart Circ Physiol, November 1, 2007; 293(5): H3001 - H3007. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. R. Lamberts, N. Hamdani, T. W. Soekhoe, N. M. Boontje, R. Zaremba, L. A. Walker, P. P. de Tombe, J. van der Velden, and G. J. M. Stienen Frequency-dependent myofilament Ca2+ desensitization in failing rat myocardium J. Physiol., July 15, 2007; 582(2): 695 - 709. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Hiranandani, S. Raman, A. Kalyanasundaram, M. Periasamy, and P. M. L. Janssen Frequency-dependent contractile strength in mice over- and underexpressing the sarco(endo)plasmic reticulum calcium-ATPase Am J Physiol Regulatory Integrative Comp Physiol, July 1, 2007; 293(1): R30 - R36. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. D. Varian and P. M. L. Janssen Frequency-dependent acceleration of relaxation involves decreased myofilament calcium sensitivity Am J Physiol Heart Circ Physiol, May 1, 2007; 292(5): H2212 - H2219. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. M. Givertz, C. Andreou, C. H. Conrad, and W. S. Colucci Direct Myocardial Effects of Levosimendan in Humans With Left Ventricular Dysfunction: Alteration of Force-Frequency and Relaxation-Frequency Relationships Circulation, March 13, 2007; 115(10): 1218 - 1224. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Leszek, J. Korewicki, A. Klisiewicz, J. Janas, A. Biederman, A. Browarek, D. Charlemagne, and P. Trouve Reduced myocardial expression of calcium handling protein in patients with severe chronic mitral regurgitation Eur. J. Cardiothorac. Surg., November 1, 2006; 30(5): 737 - 743. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Vollmann, L. Luthje, P. Schott, G. Hasenfuss, and C. Unterberg-Buchwald Biventricular Pacing Improves the Blunted Force-Frequency Relation Present During Univentricular Pacing in Patients With Heart Failure and Conduction Delay Circulation, February 21, 2006; 113(7): 953 - 959. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Dolnikov, M. Shilkrut, N. Zeevi-Levin, S. Gerecht-Nir, M. Amit, A. Danon, J. Itskovitz-Eldor, and O. Binah Functional Properties of Human Embryonic Stem Cell-Derived Cardiomyocytes: Intracellular Ca2+ Handling and the Role of Sarcoplasmic Reticulum in the Contraction Stem Cells, February 1, 2006; 24(2): 236 - 245. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. H. T. Wehrens, S. E. Lehnart, S. Reiken, J. A. Vest, A. Wronska, and A. R. Marks Inaugural Article: Ryanodine receptor/calcium release channel PKA phosphorylation: A critical mediator of heart failure progression PNAS, January 17, 2006; 103(3): 511 - 518. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B M Mayosi, A Kardos, C H Davies, F Gumedze, A Hovnanian, S Burge, and H Watkins Heterozygous disruption of SERCA2a is not associated with impairment of cardiac performance in humans: implications for SERCA2a as a therapeutic target in heart failure Heart, January 1, 2006; 92(1): 105 - 109. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Luers, F. Fialka, A. Elgner, D. Zhu, J. Kockskamper, D. von Lewinski, and B. Pieske Stretch-dependent modulation of [Na+]i, [Ca2+]i, and pHi in rabbit myocardium-a mechanism for the slow force response Cardiovasc Res, December 1, 2005; 68(3): 454 - 463. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. R. Sipido and D. Eisner Something old, something new: Changing views on the cellular mechanisms of heart failure Cardiovasc Res, November 1, 2005; 68(2): 167 - 174. [Full Text] [PDF]
|
|
|
|
|
|
M M H Cheung, J F Smallhorn, B W McCrindle, G S Van Arsdell, and A N Redington Non-invasive assessment of ventricular force-frequency relations in the univentricular circulation by tissue Doppler echocardiography: a novel method of assessing myocardial performance in congenital heart disease Heart, October 1, 2005; 91(10): 1338 - 1342. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Balasubramaniam, S. Chawla, A. A. Grace, and C. L.-H. Huang Caffeine-induced arrhythmias in murine hearts parallel changes in cellular Ca2+ homeostasis Am J Physiol Heart Circ Physiol, October 1, 2005; 289(4): H1584 - H1593. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. S. Maier, C. Wahl-Schott, W. Horn, S. Weichert, C. Pagel, S. Wagner, N. Dybkova, O. J. Muller, M. Nabauer, W.-M. Franz, et al. Increased SR Ca2+ cycling contributes to improved contractile performance in SERCA2a-overexpressing transgenic rats Cardiovasc Res, September 1, 2005; 67(4): 636 - 646. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Edes, Z. Gasior, and K. Wita Effects of nebivolol on left ventricular function in elderly patients with chronic heart failure: results of the ENECA study Eur J Heart Fail, June 1, 2005; 7(4): 631 - 639. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. M. Harris, G. D. Mills, X. Chen, H. Kubo, R. M. Berretta, V. S. Votaw, L. F. Santana, and S. R. Houser Alterations in Early Action Potential Repolarization Causes Localized Failure of Sarcoplasmic Reticulum Ca2+ Release Circ. Res., March 18, 2005; 96(5): 543 - 550. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. M. Loughrey, G. L. Smith, and K. E. MacEachern Comparison of Ca2+ release and uptake characteristics of the sarcoplasmic reticulum in isolated horse and rabbit cardiomyocytes Am J Physiol Heart Circ Physiol, September 1, 2004; 287(3): H1149 - H1159. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. W. Chaudhary, E. I. Rossman, V. Piacentino III, A. Kenessey, C. Weber, J. P. Gaughan, K. Ojamaa, I. Klein, D. M. Bers, S. R. Houser, et al. Altered myocardial Ca2+ cycling after left ventricular assist device support in the failing human heart J. Am. Coll. Cardiol., August 18, 2004; 44(4): 837 - 845. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. A. Hobai, C. Maack, and B. O'Rourke Partial Inhibition of Sodium/Calcium Exchange Restores Cellular Calcium Handling in Canine Heart Failure Circ. Res., August 6, 2004; 95(3): 292 - 299. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M.E Diaz, H.K Graham, and A.W Trafford Enhanced sarcolemmal Ca2+ efflux reduces sarcoplasmic reticulum Ca2+ content and systolic Ca2+ in cardiac hypertrophy Cardiovasc Res, June 1, 2004; 62(3): 538 - 547. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. E. J. Schultz, B. J. Glascock, S. A. Witt, M. L. Nieman, K. J. Nattamai, L. H. Liu, J. N. Lorenz, G. E. Shull, T. R. Kimball, and M. Periasamy Accelerated onset of heart failure in mice during pressure overload with chronically decreased SERCA2 calcium pump activity Am J Physiol Heart Circ Physiol, March 1, 2004; 286(3): H1146 - H1153. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. A. Jortani, S. D. Prabhu, and R. Valdes Jr Strategies for Developing Biomarkers of Heart Failure Clin. Chem., February 1, 2004; 50(2): 265 - 278. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Huke, L. H Liu, D. Biniakiewicz, W. T Abraham, and M. Periasamy Altered force-frequency response in non-failing hearts with decreased SERCA pump-level Cardiovasc Res, September 1, 2003; 59(3): 668 - 677. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Baartscheer, C. A. Schumacher, C. N.W. Belterman, R. Coronel, and J. W.T. Fiolet SR calcium handling and calcium after-transients in a rabbit model of heart failure Cardiovasc Res, April 1, 2003; 58(1): 99 - 108. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Vogel, M. M.H. Cheung, J. Li, S. B. Kristiansen, M. R. Schmidt, P. A. White, K. Sorensen, and A. N. Redington Noninvasive Assessment of Left Ventricular Force-Frequency Relationships Using Tissue Doppler-Derived Isovolumic Acceleration: Validation in an Animal Model Circulation, April 1, 2003; 107(12): 1647 - 1652. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Pieske and S. R Houser [Na+]i handling in the failing human heart Cardiovasc Res, March 15, 2003; 57(4): 874 - 886. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Schillinger, J. W Fiolet, K. Schlotthauer, and G. Hasenfuss Relevance of Na+-Ca2+ exchange in heart failure Cardiovasc Res, March 15, 2003; 57(4): 921 - 933. [Full Text] [PDF]
|
|
|
|
|
|
H. E Cingolani, N. G Perez, B. Pieske, D. von Lewinski, and M. C Camilion de Hurtado Stretch-elicited Na+/H+ exchanger activation: the autocrine/paracrine loop and its mechanical counterpart Cardiovasc Res, March 15, 2003; 57(4): 953 - 960. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M.-L. Ward, A. J Pope, D. S Loiselle, and M. B Cannell Reduced contraction strength with increased intracellular [Ca2+] in left ventricular trabeculae from failing rat hearts J. Physiol., January 15, 2003; 546(2): 537 - 550. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. Schillinger and H. Kogler Altered phosphorylation and Ca2+-sensitivity of myofilaments in human heart failure Cardiovasc Res, January 1, 2003; 57(1): 5 - 7. [Full Text] [PDF]
|
|
|
|
|
|
M. Petretta, M. L.E. Vicario, L. Spinelli, A. Ferro, A. Cuocolo, M. Condorelli, and D. Bonaduce Combined effect of the force-frequency and length-tension mechanisms on left ventricular function in patients with dilated cardiomyopathy Eur J Heart Fail, December 1, 2002; 4(6): 727 - 735. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Nemoto, G. DeFreitas, D. L. Mann, and B. A. Carabello Effects of changes in left ventricular contractility on indexes of contractility in mice Am J Physiol Heart Circ Physiol, December 1, 2002; 283(6): H2504 - H2510. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Pieske and J. Kockskamper Alternans Goes Subcellular: A "Disease" of the Ryanodine Receptor? Circ. Res., October 4, 2002; 91(7): 553 - 555. [Full Text] [PDF]
|
|
|
|
|
|
M.E. Diaz, D.A. Eisner, and S.C. O'Neill Depressed Ryanodine Receptor Activity Increases Variability and Duration of the Systolic Ca2+ Transient in Rat Ventricular Myocytes Circ. Res., October 4, 2002; 91(7): 585 - 593. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Kindermann, B. Schwaab, N. Finkler, S. Schaller, M. Bohm, and G. Frohlig Defining the optimum upper heart rate limit during exercise. A study in pacemaker patients with heart failure Eur. Heart J., August 2, 2002; 23(16): 1301 - 1308. [Abstract] [PDF]
|
|
|
|
|
|
B. Pieske, L. S. Maier, V. Piacentino III, J. Weisser, G. Hasenfuss, and S. Houser Rate Dependence of [Na+]i and Contractility in Nonfailing and Failing Human Myocardium Circulation, July 23, 2002; 106(4): 447 - 453. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. R. Alpert, L. A. Mulieri, and D. Warshaw The failing human heart Cardiovasc Res, April 1, 2002; 54(1): 1 - 10. [Full Text] [PDF]
|
|
|
|
|
|
G. Hasenfuss, L. S. Maier, H.-P. Hermann, C. LUers, M. HUnlich, O. Zeitz, P. M.L. Janssen, and B. Pieske Influence of Pyruvate on Contractile Performance and Ca2+ Cycling in Isolated Failing Human Myocardium Circulation, January 15, 2002; 105(2): 194 - 199. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Somura, H. Izawa, M. Iwase, Y. Takeichi, R. Ishiki, T. Nishizawa, A. Noda, K. Nagata, Y. Yamada, and M. Yokota Reduced Myocardial Sarcoplasmic Reticulum Ca2+-ATPase mRNA Expression and Biphasic Force-Frequency Relations in Patients With Hypertrophic Cardiomyopathy Circulation, August 7, 2001; 104(6): 658 - 663. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Forini, A. Paolicchi, T. Pizzorusso, G. M. Ratto, M. Saviozzi, V. Vanini, and G. Iervasi 3,5,3'-Triiodothyronine deprivation affects phenotype and intracellular [Ca2+]i of human cardiomyocytes in culture Cardiovasc Res, August 1, 2001; 51(2): 322 - 330. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. J. Baker, C. H. Redfern, M. D. Harwood, P. C. Simpson, and B. R. Conklin Abnormal contraction caused by expression of Gi-coupled receptor in transgenic model of dilated cardiomyopathy Am J Physiol Heart Circ Physiol, April 1, 2001; 280(4): H1653 - H1659. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Periasamy Adenoviral-Mediated SERCA Gene Transfer Into Cardiac Myocytes : How Much Is Too Much? Circ. Res., March 2, 2001; 88(4): 373 - 375. [Full Text] [PDF]
|
|
|
|
|
|
S. R Houser Reduced abundance of transverse tubules and L-type calcium channels: another cause of defective contractility in failing ventricular myocytes Cardiovasc Res, February 1, 2001; 49(2): 253 - 256. [Full Text] [PDF]
|
|
|
|
|
|
S. E. Litwin, D. Zhang, and J. H. B. Bridge Dyssynchronous Ca2+ Sparks in Myocytes From Infarcted Hearts Circ. Res., November 24, 2000; 87(11): 1040 - 1047. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. R. Sipido, P. G. A. Volders, S. H. M. de Groot, F. Verdonck, F. Van de Werf, H. J. J. Wellens, and M. A. Vos Enhanced Ca2+ Release and Na/Ca Exchange Activity in Hypertrophied Canine Ventricular Myocytes : Potential Link Between Contractile Adaptation and Arrhythmogenesis Circulation, October 24, 2000; 102(17): 2137 - 2144. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I. Sjaastad, O. M. Sejersted, A. Ilebekk, and R. Bjornerheim Echocardiographic criteria for detection of postinfarction congestive heart failure in rats J Appl Physiol, October 1, 2000; 89(4): 1445 - 1454. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Ito, X. Yan, M. Tajima, Z. Su, W. H. Barry, and B. H. Lorell Contractile Reserve and Intracellular Calcium Regulation in Mouse Myocytes From Normal and Hypertrophied Failing Hearts Circ. Res., September 29, 2000; 87(7): 588 - 595. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. S. Maier, P. Barckhausen, J. Weisser, I. Aleksic, M. Baryalei, and B. Pieske Ca2+ handling in isolated human atrial myocardium Am J Physiol Heart Circ Physiol, September 1, 2000; 279(3): H952 - H958. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Sen, G. Cui, G. C. Fonarow, and H. Laks Differences in mechanisms of SR dysfunction in ischemic vs. idiopathic dilated cardiomyopathy Am J Physiol Heart Circ Physiol, August 1, 2000; 279(2): H709 - H718. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Barrere-Lemaire, C. Piot, F. Leclercq, J. Nargeot, and S. Richard Facilitation of L-type calcium currents by diastolic depolarization in cardiac cells: impairment in heart failure Cardiovasc Res, August 1, 2000; 47(2): 336 - 349. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. J. Hajjar, R. H.G. Schwinger, U. Schmidt, C. S. Kim, D. Lebeche, A. A. Doye, and J. K. Gwathmey Myofilament Calcium Regulation in Human Myocardium Circulation, April 11, 2000; 101(14): 1679 - 1685. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Z Kassiri, R Myers, R Kaprielian, H S Banijamali, and P H Backx Rate-dependent changes of twitch force duration in rat cardiac trabeculae: a property of the contractile system J. Physiol., April 1, 2000; 524(1): 221 - 231. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. S Maier, C. Schwan, W. Schillinger, K. Minami, U. Schutt, and B. Pieske Gingerol, isoproterenol and ouabain normalize impaired post-rest behavior but not force-frequency relation in failing human myocardium Cardiovasc Res, March 1, 2000; 45(4): 913 - 924. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
U Ravens and D Dobrev Regulation of sarcoplasmic reticulum Ca2+-ATPase and phospholamban in the failing and nonfailing heart Cardiovasc Res, January 1, 2000; 45(1): 245 - 252. [Full Text] [PDF]
|
|
|
|
|
|
W. V. Houck, L. C. Pan, S. B. Kribbs, M. J. Clair, G. M. McDaniel, R. S. Krombach, W. M. Merritt, C. Pirie, J. P. Iannini, R. Mukherjee, et al. Effects of Growth Hormone Supplementation on Left Ventricular Morphology and Myocyte Function With the Development of Congestive Heart Failure Circulation, November 9, 1999; 100(19): 2003 - 2009. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Bartling, H. Milting, H. Schumann, D. Darmer, L. Arusoglu, M. M. Koerner, A. El-Banayosy, R. Koerfer, J. Holtz, and H.-R. Zerkowski Myocardial Gene Expression of Regulators of Myocyte Apoptosis and Myocyte Calcium Homeostasis During Hemodynamic Unloading by Ventricular Assist Devices in Patients With End-Stage Heart Failure Circulation, November 9, 1999; 100 (2009): II-216 - II-223. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Krieg, T. Wahlers, W. Giess, R. Rohde, M. Hartrumpf, M. Bund, and A. Haverich Inhaled nitric oxide and inhaled prostaglandin E1: effect on left ventricular contractility when used for treatment of experimental pulmonary hypertension Eur. J. Cardiothorac. Surg., November 1, 1999; 14(5): 494 - 502. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. A. Fallavollita, S. Jacob, R. F. Young, and J. M. Canty Jr. Regional alterations in SR Ca2+-ATPase, phospholamban, and HSP-70 expression in chronic hibernating myocardium Am J Physiol Heart Circ Physiol, October 1, 1999; 277(4): H1418 - H1428. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. H. Kim, W. H. Devlin, S. K. Das, J. Petrusha, D. Montgomery, and M. R. Starling Effects of {beta}-Adrenergic Blocking Therapy on Left Ventricular Diastolic Relaxation Properties in Patients With Dilated Cardiomyopathy Circulation, August 17, 1999; 100(7): 729 - 735. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Prestle, S. Dieterich, M. Preuss, U. Bieligk, and G. Hasenfuss Heterogeneous transmural gene expression of calcium-handling proteins and natriuretic peptides in the failing human heart Cardiovasc Res, August 1, 1999; 43(2): 323 - 331. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Flesch, C. Maack, B. Cremers, A. T. Baumer, M. Sudkamp, and M. Bohm Effect of {beta}-Blockers on Free Radical–Induced Cardiac Contractile Dysfunction Circulation, July 27, 1999; 100(4): 346 - 353. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Pieske, L. S. Maier, D. M. Bers, and G. Hasenfuss Ca2+ Handling and Sarcoplasmic Reticulum Ca2+ Content in Isolated Failing and Nonfailing Human Myocardium Circ. Res., July 9, 1999; 85(1): 38 - 46. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Meissner, J.-Y. Min, N. Haake, S. Hirt, and R. Simon Dantrolene sodium improves the force-frequency relationship and {beta}-adrenergic responsiveness in failing human myocardium Eur J Heart Fail, June 1, 1999; 1(2): 177 - 186. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Murakami, J. Zhang, M. H. J. Eijgelshoven, W. Chen, W. C. Carlyle, Y. Zhang, G. Gong, and R. J. Bache Myocardial creatine kinase kinetics in hearts with postinfarction left ventricular remodeling Am J Physiol Heart Circ Physiol, March 1, 1999; 276(3): H892 - H900. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. R. Houser and E. G. Lakatta Function of the Cardiac Myocyte in the Conundrum of End-Stage, Dilated Human Heart Failure Circulation, February 9, 1999; 99(5): 600 - 604. [Full Text] [PDF]
|
|
|
|
|
|
G. Hasenfuss, W. Schillinger, S. E. Lehnart, M. Preuss, B. Pieske, L. S. Maier, J. Prestle, K. Minami, and H. Just Relationship Between Na+-Ca2+–Exchanger Protein Levels and Diastolic Function of Failing Human Myocardium Circulation, February 9, 1999; 99(5): 641 - 648. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Anger, A.-M. Lompre, O. Vallot, F. Marotte, L. Rappaport, and J.-L. S. MD Cellular Distribution of Ca2+ Pumps and Ca2+ Release Channels in Rat Cardiac Hypertrophy Induced by Aortic Stenosis Circulation, December 1, 1998; 98(22): 2477 - 2486. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. D. Prabhu Ryanodine and the left ventricular force-interval and relaxation-interval relations in closed-chest dogs: insights on calcium handling Cardiovasc Res, December 1, 1998; 40(3): 483 - 491. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Hasenfuss, B. Pieske, M. Castell, B. Kretschmann, L. S. Maier, and H. Just Influence of the Novel Inotropic Agent Levosimendan on Isometric Tension and Calcium Cycling in Failing Human Myocardium Circulation, November 17, 1998; 98(20): 2141 - 2147. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Hasenfuss Calcium Pump Overexpression and Myocardial Function : Implications for Gene Therapy of Myocardial Failure Circ. Res., November 2, 1998; 83(9): 966 - 968. [Full Text] [PDF]
|
|
|
|
|
|
C Mittmann, T Eschenhagen, and H Scholz Cellular and molecular aspects of contractile dysfunction in heart failure Cardiovasc Res, August 1, 1998; 39(2): 267 - 275. [Full Text] [PDF]
|
|
|
|
|
|
G. Hasenfuss Animal models of human cardiovascular disease, heart failure and hypertrophy Cardiovasc Res, July 1, 1998; 39(1): 60 - 76. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Dipla, J. A. Mattiello, V. Jeevanandam, S. R. Houser, and K. B. Margulies Myocyte Recovery After Mechanical Circulatory Support in Humans With End-Stage Heart Failure Circulation, June 16, 1998; 97(23): 2316 - 2322. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. R. C. Dekker, H. Rademaker, J. T. Vermeulen, T. Opthof, R. Coronel, J. A. E. Spaan, and M. J. Janse Cellular Uncoupling During Ischemia in Hypertrophied and Failing Rabbit Ventricular Myocardium : Effects of Preconditioning Circulation, May 5, 1998; 97(17): 1724 - 1730. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. S. Maier, R. Brandes, B. Pieske, and D. M. Bers Effects of left ventricular hypertrophy on force and Ca2+ handling in isolated rat myocardium Am J Physiol Heart Circ Physiol, April 1, 1998; 274(4): H1361 - H1370. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Hasenfuss Alterations of calcium-regulatory proteins in heart failure Cardiovasc Res, February 1, 1998; 37(2): 279 - 289. [Full Text] [PDF]
|
|
|
|
|
|
C.W. Balke and S. R. Shorofsky Alterations in calcium handling in cardiac hypertrophy and heart failure Cardiovasc Res, February 1, 1998; 37(2): 290 - 299. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Richard, F. Leclercq, S. Lemaire, C. Piot, and J. Nargeot Ca2+ currents in compensated hypertrophy and heart failure Cardiovasc Res, February 1, 1998; 37(2): 300 - 311. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. D Wickenden, R. Kaprielian, Z. Kassiri, J. N Tsoporis, R. Tsushima, G. I Fishman, and P. H Backx The role of action potential prolongation and altered intracellular calcium handling in the pathogenesis of heart failure Cardiovasc Res, February 1, 1998; 37(2): 312 - 323. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. M Phillips, P. Narayan, A. M Gomez, K. Dilly, L. R Jones, W.J. Lederer, and R. A Altschuld Sarcoplasmic reticulum in heart failure: central player or bystander? Cardiovasc Res, February 1, 1998; 37(2): 346 - 351. [Full Text] [PDF]
|
|
|
|
|
|
M. A Movsesian and R. H.G Schwinger Calcium sequestration by the sarcoplasmic reticulum in heart failure Cardiovasc Res, February 1, 1998; 37(2): 352 - 359. [Full Text] [PDF]
|
|
|
|
|
|
M. Meyer and W. H Dillmann Sarcoplasmic reticulum Ca2+-ATPase overexpression by adenovirus mediated gene transfer and in transgenic mice Cardiovasc Res, February 1, 1998; 37(2): 360 - 366. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. P de Tombe Altered contractile function in heart failure Cardiovasc Res, February 1, 1998; 37(2): 367 - 380. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. C. Schaub, M. A. Hefti, R. A. Zuellig, and I. Morano Modulation of contractility in human cardiac hypertrophy by myosin essential light chain isoforms Cardiovasc Res, February 1, 1998; 37(2): 381 - 404. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Neumann, U. Ravens, and G. Heusch Characterization of excitation-contraction coupling in conscious dogs with pacing-induced heart failure Cardiovasc Res, February 1, 1998; 37(2): 456 - 466. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. R Sipido, T. Stankovicova, W. Flameng, J. Vanhaecke, and F. Verdonck Frequency dependence of Ca2+ release from the sarcoplasmic reticulum in human ventricular myocytes from end-stage heart failure Cardiovasc Res, February 1, 1998; 37(2): 478 - 488. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Holubarsch, J Ludemann, S Wiessner, T. Ruf, H Schulte-Baukloh, S Schmidt-Schweda, B Pieske, H Posival, and H Just Shortening versus isometric contractions in isolated human failing and non-failing left ventricular myocardium: dependency of external work and force on muscle length, heart rate and inotropic stimulation Cardiovasc Res, January 1, 1998; 37(1): 46 - 57. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Pauschinger, A. Doerner, A. Remppis, R. Tannhauser, U. Kuhl, and H.-P. Schultheiss Differential myocardial abundance of collagen type I and type III mRNA in dilated cardiomyopathy: effects of myocardial inflammation Cardiovasc Res, January 1, 1998; 37(1): 123 - 129. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. G. Spinale, R. Mukherjee, J. P. Iannini, S. Whitebread, L. Hebbar, M. J. Clair, D. M. Melton, M. H. Cox, P. B. Thomas, and P. B. Marc de Gasparo Modulation of the Renin-Angiotensin Pathway Through Enzyme Inhibition and Specific Receptor Blockade in Pacing-Induced Heart Failure : II. Effects on Myocyte Contractile Processes Circulation, October 7, 1997; 96(7): 2397 - 2406. [Abstract] [Full Text]
|
|
|
|
 |
|
 R. H. G. Schwinger, K. Brixius, U. Bavendiek, S. Hoischen, J. Müller-Ehmsen, B. Bölck, and E. Erdmann Effect of Cyclopiazonic Acid on the Force-Frequency Relationship in Human Nonfailing Myocardium J. Pharmacol. Exp. Ther., October 1, 1997; 283(1): 286 - 292. [Abstract] [Full Text]
|
|
|
|
|
|
K. Brixius, M. Pietsch, S. Hoischen, J. Muller-Ehmsen, and R. H. G. Schwinger Effect of inotropic interventions on contraction and Ca2+ transients in the human heart J Appl Physiol, August 1, 1997; 83(2): 652 - 660. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K Davia, C.H Davies, and S.E Harding Effects of inhibition of sarcoplasmic reticulum calcium uptake on contraction in myocytes isolated from failing human ventricle Cardiovasc Res, January 1, 1997; 33(1): 88 - 97. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Hasenfuss, L. A. Mulieri, P. D. Allen, H. Just, and N.R. Alpert Influence of Isoproterenol and Ouabain on Excitation-Contraction Coupling, Cross-Bridge Function, and Energetics in Failing Human Myocardium Circulation, December 15, 1996; 94(12): 3155 - 3160. [Abstract] [Full Text]
|
|
|
|
|
|
S. M. Pogwizd, K. Schlotthauer, L. Li, W. Yuan, and D. M. Bers Arrhythmogenesis and Contractile Dysfunction in Heart Failure : Roles of Sodium-Calcium Exchange, Inward Rectifier Potassium Current, and Residual {beta}-Adrenergic Responsiveness Circ. Res., June 8, 2001; 88(11): 1159 - 1167. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Vogel, M. R. Schmidt, S. B. Kristiansen, M. Cheung, P. A. White, K. Sorensen, and A. N. Redington Validation of Myocardial Acceleration During Isovolumic Contraction as a Novel Noninvasive Index of Right Ventricular Contractility: Comparison With Ventricular Pressure-Volume Relations in an Animal Model Circulation, April 9, 2002; 105(14): 1693 - 1699. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||